Fibrinogen concentrate for paediatric congenital fibrinogen deficiency

Efficacy and safety of fibrinogen concentrate for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency

Djambas Khayat C, Lohade S, D’Souza F, Shamanur LG, Zekavat OR, Kruzhkova I, et al. Haemophilia 2021;27:283–292.

• Congenital fibrinogen deficiency (CFD) is a rare blood clotting disorder
• Human fibrinogen concentrate (HFC) is the current standard of care for adults with CFD
• This was a prospective Phase 3 efficacy, safety, and pharmacokinetic study of on-demand treatment or surgical prophylaxis with HFC in children with CFD
• Outcomes in children were comparable to previous data in adult/adolescent patients

Fibrinogen deficiency is associated with inadequate blood clot formation, resulting in spontaneous and excessive bleeding episodes of varying frequencies and severities (Peyvandi et al., 2006), even after minor injuries.

CFD is an ultra-rare condition with an estimated prevalence of 1–2 per million (Mannucci et al., 2004). There are two major types of CFD (Casini et al., 2018):

• afibrinogenaemia (complete absence of fibrinogen)
• hypofibrinogenaemia (proportional decrease of functional and antigenic fibrinogen levels)

Fibrinogen replacement therapy with HFC is the current standard of care for adults with CFD. Plasma-derived, virus-inactivated HFCs are proven to be efficacious with favourable safety profiles in adults and adolescents with CFD (Djambas Khayat et al., 2019; Lissitchkov et al., 2020), and address the risk of pathogen transmission previously associated with cryoprecipitate or fresh frozen plasma.

These products provide well-defined fibrinogen content with few extraneous proteins and permit accurate, standardised dosing with small infusion volumes (Bornikova et al., 2011; Franchini et al., 2012). HFC products also enable rapid preparation times without the requirement of blood group matching or thawing (Franchini et al., 2012).

In this multinational, prospective, open-label, Phase 3 study, Djambas Khayat and colleagues assessed the efficacy and safety of HFC for on-demand acute treatment of bleeding episodes and surgical prophylaxis in paediatric patients (<12 years) with CFD.

The study screened 15 patients with a diagnosis of afibrinogenaemia; 1 patient was not treated with HFC. In total, 3 discontinued prematurely (withdrawal of consent [n=2]; serious adverse event [n=1]) and 11 completed the study (Figure 1).

Figure 1. Patient disposition. † Patients received HFC for PK analysis, treatment of a bleeding episodes or surgical prophylaxis. ‡ One patient did not participate in the PK analysis but was included in the safety population. BE, bleeding episode; FAS, full analysis set; PK, pharmacokinetic.

Haemostatic efficacy of HFC for on-demand treatment of bleeding and surgical prophylaxis was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) based on an objective 4-point efficacy scale. An additional surrogate marker for haemostatic efficacy (maximum clot firmness [MCF]), single-dose pharmacokinetics, and safety were also assessed.

Haemostatic efficacy was 100% successful for both on-demand treatment of bleeding episodes (95% CI: 69.2–100.0) and surgical prophylaxis (95% CI: 29.2–100.0), as assessed by IDMEAC.

• For bleeding episodes, mean MCF was significantly increased from pre-treatment values to 1-hour post-infusion (P=0.0002), coinciding with haemostatic efficacy
• 100% overall success rate for surgical prophylaxis

Figure 2. Mean fibrinogen activity during pharmacokinetic assessment (N = 13) disposition. Data present actual values for fibrinogen activity. Values <30 mg/dL were below the limit of detection. SE, standard error.

Both the safety and pharmacokinetic profile for HFC was considered favourable by Djambas Khayat and colleagues (Figure 2). Compared with a previous study in adults/adolescents (N=22 patients aged 12–53 years), HFC was associated with lower in vivo recovery of fibrinogen and haemoglobin levels, a reduced peak plasma concentration (C_max) and exposure, a shorter half-life, and faster clearance in paediatric patients (Ross et al., 2018).

Key take-aways

– A prospective study evaluating treatment of CFD showed that HFC was associated with significant increases in fibrinogen plasma levels and markers of global haemostasis

– HFC was efficacious for paediatric CFD patients:
- in the treatment of on-demand acute bleeding
- for perioperative prophylaxis

– HFC showed a favourable pharmacokinetic and safety profile in children with CFD

References

Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost. 2011;9(9):1687–1704.

Casini A, Undas A, Palla R, Thachil J, de Moerloos P. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(9):1887–1890.

Djambas Khayat C, El Khorassani M, Lambert T, Gay V, Barthez-Toullc M, La Mazure J, et al. Clinical pharmacology, efficacy and safety study of a triple-secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency. J Thromb Haemost. 2019;17(4):635–644.

Franchini M, Lippi G. Fibrinogen replacement therapy: a critical review of the literature. Blood Transfus. 2012;10(1):23–27.

Lissitchkov T, Madan B, Djambas Khayat C, Zozulya N, Ross C, Karimi M, et al. Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients. J Thromb Haemost. 2020;18:815–824.

Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood. 2004;104:1243–1252.

Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb and Haemost. 2006;4(7):1634–1637.

Ross C, Rangarajan S, Karimi M, Toogeh G, Apte S, Lissitchkov T, et al. Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency. J Thromb Haemost. 2018;16(2):253–261.